Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
  • C07F9/6539—Five-membered rings
  • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6503—Five-membered rings
  • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6503—Five-membered rings
  • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
  • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
  • C07F9/6539—Five-membered rings

Definitions

• This invention relates to novel S-heterocyclic derivatives of phosphine or phosphite gold mercaptides which have useful pharmacological activity. More specifically, the compounds of this invention have antiarthritic activity as measured by their ability to inhibit adjuvant-induced polyarthritis in rats.
• R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl or alkoxy having from one to three carbon atoms;
• X is S, NH, NCH or O
• R and R are hydrogen or together form a 1,2-benzo radical
• Preferred compounds of this invention are represented by Formula I where R is lower alkyl. Also preferred are those compounds of Formula I where the heterocyclic moiety is 2-thiaz olinyl, 2-benzimidazolyl and 2-benzoxazolyl.
• the compounds of this invention are prepared by reaction of an heterocyclic mercaptan compound with an appropriate phosphine or phosphite gold(l) halide, preferably chloride, in the presence of alkali such assodium hydroxide in a solvent such as aqueous alcoholchloroform at about 25 for approximately 1 hour in a nitrogen atmosphere.
• an appropriate phosphine or phosphite gold(l) halide preferably chloride
• the phosphine or phosphite gold halides employed as starting materials are prepared by reaction of a cold (10 to 5) solution of gold(l) chloride, prepared by mixing thiodiglycol and gold acid chloride trihydrate in aqueous alcohol, with an appropriate phosphine or.
• phosphite such as triethylphosphine.
• Other procedures which may be applied to the preparation of these intermediates are found in J. Chem. Soc. 1828 (1937) and 1235 (1940) and Australian J. Chem. 19:547 (1966).
• the anti-arthritic activity of the compounds of this invention is measured by their ability to inhibit adjuvant-induced polyarthritis in rats.
• the compounds of Formula I produce marked inhibition of the development of adjuvant arthritis in rats at daily oral doses as low as about 20 mg. per kilogram of body weight. Of particular importance isthe attainment of significant serum levels of gold following oral administration of these doses.
• Adjuvant arthritis in rats is produced by a single injection of 0.75 mg. of Mycobacterium butyricum suspended in white paraffin (NF) into a hindpaw (left footpad).
• the injected leg becomes inflamed and reaches a maximum volume in 3 to 5 days (primary lesion).
• the animals exhibit a decrease in body weight gain during this initial period.
• Adjuvant arthritis (secondary phase) occurs after a delay of approximately 10 days and is characterized by inflammation of the noninjected sites (right hind leg), decrease in body weight gain and further increases in the volume of the injected hind leg.
• the compounds of Formula I administered in the doses described above beginning on the day of ad- 5 juvant injection and continuing for 17 days thereafter,
• the compounds of this invention are administered in conventional dosage unit forms by incorporating an amount sufficient to produce anti-arthritic activity, without toxic effects, with a nontoxic pharmaceutical carrier according to accepted procedures.
• the dosage units will contain an S-heterocyclic derivative of a phosphine or phosphite gold mercaptide of Formula I in an amount of from about 0.5 mg. to about 25 mg., preferably 0.5 mg. to 10 mg. calculated on gold content, per unit.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil,
• the carrier or dili uent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• a wide variety of pharmaceutical forms can be employed.
• a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
• a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
• the method of producing anti-arthritic activity in ac-' cordance with this invention comprises administering internally to an animal organism an S-heterocyclic derivative of a phosphine or phosphite gold mercaptide of Formula I, usually combined with a pharmaceutical carrier, in an amount sufficient to produce antiarthritic activity without limiting side effects.
• the active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred.
• Advantageously equal doses will be administered one or two times daily with the daily dosage regimen being from about 0.5 mg. to about 50 mg., preferably 0.5 mg. to about 20 mg., calculated on gold content.
• the pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
• reaction mixture was stirred at 25 for l-hour under nitrogen, filtered and the filtrate was evaporated to dryness to give a residue which was dissolved in methanol and treated with activated charcoal to give the title compound as white crystals, m.p. l00l02 (methanol).
• EXAMPLE 5 A mixture of 11.82 g. (0.03 mol.) of gold acid chloride trihydrate and 1.9 g. (0.065 mol.) of thiodiglycol in m1. of aqueous ethanol (3:2) was stirred until the color of auric gold disappeared. The almost colorless solution was cooled below 5 and an equally cold solution of 5.6 g. (0.035 mol.) of triisopropylphosphine in 20 ml. of ethanol was added dropwise. The volume of the final reaction mixture was increased to 250 ml. with 1:1 aqueous ethanol in order to maintain a fluid mixture. After addition the mixture was stirred in the cold for 45 minutes.
• 2-benzoxazolylthio(triisopropylphosphine)gold is prepared by substitution of an equivalent amount of chloro(triisopropylphosphine)gold in the procedure of Example 3 for chloro(triethylphosphine)- gold.
• 2-benzimidazolylthio(triphenylphosphine)-gold and 2 benzoxazolylthio(triphenylphosphine)gold are obtained by substitution of equivalent amounts of chloro(triphenylphosphine)gold in the procedures of Examples 2 and 3, respectively, for chloro(t riethylphosphine)gold.
• 2-benzimidazolylthio(diethylphenylphosphine(gold and 2-benzoxazolylthio(diethylphenylphosphine)gold are obtained by substitution of equivalent amounts of chloro(diethylphenylphosphine)gold in the procedures of Examples 2 and 3, respectively, for ch ro(triethylphosphine)gold.
• bromo(trialkylphosphine)- gold complexes are prepared, for example, br0mo(triethylphosphine)gold.
• the mercapto heterocycles listed above may be allowed to react with the other phosphine or phosphite gold halides disclosed herein.
• R is lower alkyl, lower alkoxy, phenyl or phenoxy, with each alkyl or alkoxy having from one to three carbon atoms;
• R is lower alkyl.
• a compound as claimed in claim 2 where the heterocyclic moiety is 2-thiazolinyl, 2-benzimidazolyl or 2-benzoxazolyl.
• a compound as claimed in claim 3 being the compound Z-thiazolinylthio(triethylphosphine)gold.
• a compound as claimed in claim 3 being the compound 2-benzimidazolylthio'(triethylphosphine)gold.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Rheumatology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Pain & Pain Management (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (2)

• 1973
  • 1973-08-01 US US384666A patent/US3883546A/en not_active Expired - Lifetime
• 1974
  • 1974-07-18 ZA ZA00744598A patent/ZA744598B/xx unknown
  • 1974-07-26 JP JP49085967A patent/JPS5761035B2/ja not_active Expired
  • 1974-07-29 BE BE147055A patent/BE818218A/xx not_active IP Right Cessation
  • 1974-07-30 SE SE7409800A patent/SE7409800L/xx unknown
  • 1974-07-31 CA CA206060A patent/CA1054609A/en not_active Expired
  • 1974-07-31 GB GB3376374A patent/GB1422899A/en not_active Expired
  • 1974-08-01 FR FR7426773A patent/FR2240014B1/fr not_active Expired
  • 1974-08-01 DE DE2437147A patent/DE2437147C2/de not_active Expired

Patent Citations (2)

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